Giving Antibiotics a Second Chance: Evolutionary Trade-Offs and Phage-Driven Restoration of Antibiotic Susceptibility

Antimicrobial resistance poses a critical and escalating threat to global public health, driven by the widespread and often unjustified use of antibiotics and the rapid dissemination of resistance determinants. With the antibiotic discovery pipeline largely depleted, alternative and complementary strategies are urgently needed to preserve the effectiveness of existing antimicrobials. Bacteriophages-viruses that specifically infect bacteria-have re-emerged as promising tools not only for direct bacterial eradication but also for reshaping bacterial evolutionary trajectories. This review examines the concept of phage-driven restoration of antibiotic susceptibility, focusing on evolutionary trade-offs that arise when bacteria adapt to phage pressure. Resistance to bacteriophages frequently involves modifications of surface structures, capsules, or efflux systems, changes that often incur fitness costs manifested as reduced virulence, impaired biofilm formation, or increased antibiotic sensitivity. Experimental studies and clinical case reports demonstrate that phage-antibiotic synergy can suppress bacterial growth more effectively than monotherapy, limit resistance emergence, and resensitize multidrug-resistant pathogens to previously ineffective antibiotics. Particular attention is given to mechanisms involving efflux pump targeting, capsule loss, biofilm disruption, and temperate phage-antibiotic interactions. In addition, emerging strategies that combine bacteriophages with CRISPR-Cas systems enable precise targeting and removal of resistance genes, offering a highly selective means to restore antibiotic efficacy and curb horizontal gene transfer. Together, these findings highlight bacteriophages as powerful evolutionary and therapeutic tools capable of giving antibiotics a "second chance". Integrating phage-based approaches into antibiotic stewardship frameworks may represent a sustainable path forward in combating multidrug-resistant bacterial infections.